Pharmacogenetics involves the study of host susceptibility and environmental exposure in cancer development. The unique contribution of this discipline is that the genes studied are common, the role of the environment more explicit because the mechanism of the polymorphic enzymes of interest is known, and the study base is the population rather than the family. A broad range of studies of pharmacogenetic variability and the relationship to carcinogenesis is underway. We are examining a variety of putative susceptibility genes in a case-control study of lung cancer. We have observed increased risk of lung cancer in GSTM1 null individuals. Other genes, including GSTP1, CYP1A1, CYP2D6, CYP2A6, and the Ah receptor, are under investigation. Putative genetic susceptibility markers are also the focus of study with regard to other cancers including: head and neck, nasopharyngeal, prostate, breast, and colon. We originally reported one of the first relationships of exposure-gene effects relevant to cancer with a description of the relationship of the NAT-2 (N-acetyltransferase) genotype/phenotype, 4-aminobiphenyl hemoglobin adducts, and tobacco consumption. We are examining the relationship of other carcinogenic exposures to genetic factors including the environmental toxicant dioxin (in the exposed population of Seveso, Italy) and nicotine (in a smoking cessation study). The relationship of effect markers (i.e., oncogene mutations in tumor tissue) to both genetic factors and exposures is being considered in well-characterized series of colon, gastric and lung cancers.